The invention relates to the identification and the use of compounds which are modulators of a SOX transcription factor, for the treatment of alopecia. It also relates to methods for the in vitro diagnosis or in vitro prognosis of this pathological condition.
In human beings, hair growth is cyclical and comprises three successive phases: the anagen phase, the catagen phase and the telogen phase. Each follicle of the head of hair is therefore continuously renewed, in a cyclical manner and independently of the adjacent follicles (Kligman 1959, Montagna and Parakkal, 1974). The anagen phase or growth phase, during which the hair extends, lasts several years. This phase recapitulates the morphogenesis of the hair and is divided into 7 different stages (anagen I to anagen VII) (Muller-Rover et al., 2001). To simplify, the anagen phase is generally reduced to three steps which each group together several stages: early for steps I-III, mid-anagen for steps IV to V and late anagen for steps VI and VII.
The catagen phase which follows on from the anagen phase is very short and lasts only a few weeks. This phase is divided into 8 different stages (catagen I to catagen VIII) (Muller-Rover et al., 2001). During this phase, the hair undergoes involution, the follicle atrophies and its dermal implantation appears increasingly high. The telogen phase, which lasts a few months, corresponds to a resting period for the follicle, where the hair ends up falling out. After this resting phase, a new follicle is regenerated, on site, and a new cycle recommences (Montagna and Parakkal, 1974).
At each moment, not all the hairs are in the same phase at the same time. Thus, out of the approximately 150 000 hairs which make up a head of hair, only approximately 10% of them are at rest and will therefore be replaced in a few months according to a biological clock specific to each hair (Montagna, 1974).
In mice and the other mammals with fur, the hair follicles also have a renewal cycle comprising the three anagen, catagen and telogen phases, divided up into various stages. On the other hand, the hair cycles of young animals are often “synchronized”, i.e. in the same phase of the cycle at the same moment in the same region (Muller-Rover et al., 2001).
Natural hair loss is a physiological phenomenon which occurs continuously and can be estimated, on average, at a few hundred hairs per day for a normal physiological state. However, it so happens that the hair cycle can become disturbed and that hair loss accelerates and results in a temporary or permanent hair loss called alopecia. Various causes may be responsible for alopecia.
Various types of alopecia exist, the main forms being:
hereditary androgenetic alopecia, which is the most common: it manifests itself through a decrease in hair volume, or even baldness, and effects 70% of men;
acute alopecia: it can be associated with chemotherapy treatment, stress, substantial dietary deficiencies, iron deficiency, hormonal disorders, AIDS, acute irradiation;
alopecia areata which appears to be of autoimmune origin (cell-mediated mechanism), which is characterized by more or less large patches of baldness in one or more areas. This form of alopecia can affect the entire head, in which case the term alopecia totalis is used, and sometimes the entire body, then being referred to as alopecia universalis, and in this case there is no longer any body hair or head hair on the entire body.
In all these three cases, the hair loss is directly related to the hair cycle, the follicle no longer entering into the anagen phase, or the anagen phase not being maintained, which implies that the follicle no longer produces a hair shaft and therefore no longer produces hair. In order to combat alopecia, it is therefore necessary to reinitiate the hair cycle by activating the anagen phase.
Compositions which make it possible to suppress or reduce alopecia, and in particular to induce or stimulate entry into the anagen phase or hair growth, have been sought for many years in the cosmetics or pharmaceutical industry.
The applicant has now found that the gene encoding SOX is expressed specifically in hair follicle keratinocytes, and that its expression is induced at the moment of entry into anagen, in vivo, in a model of anagen entry induction by gonadectomy. It consequently proposes targeting this gene or its expression product, for preventing or improving alopecia phenomena.
The term “alopecia” is intended to mean all the forms of alopecia, namely, in particular, androgenetic alopecia, acute alopecia or alopecia areata.
The Sox Genes:
The Sox (for “Sry-related high mobility group (HMG) box”) gene family gets its name from the first member isolated, namely the Y-chromosome-related sex-determining Sry gene in mammals. The Sox genes are characterized by a conserved DNA sequence encoding an “HMG” domain of 79 amino acids responsible for sequence-specific DNA binding. The SOX proteins can be classified into eight groups, reviewed in Lefebvre et al, the International Journal of Biochemistry & Cell biology, 2007, 39: 2195-2214. Most have a transactivation domain or a transrepression domain, and act as transcription factors. Each gene has a particular expression profile, and distinct molecular properties.
The sequences of the Sox genes and of the proteins encoded by these genes are known. Many references also describe their properties (see Table 1).
Sox gene classification
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